Quantitative Modeling of External Ventricular Drain Output to Predict Shunt Dependency in Aneurysmal Subarachnoid Hemorrhage: Cohort Study.

BACKGROUND: Acute hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH); however, attempts to predict shunt-dependent chronic hydrocephalus using clinical parameters have been equivocal. METHODS: Cohort study of aSAH is treated with external ventricular drainage (EVD) placement at our institution, 2001-2016, via logistic regression. EVD-related parameters included mean/total EVD output (days 0-2), EVD days, EVD days ≤ 5 mmHg, and wean/clamp fails. aSAH outcomes assessed included ventriculoperitoneal shunt (VPS) placement, delayed cerebral ischemia (DCI), radiographic infarction (RI), symptomatic vasospasm (SV), age, and aSAH grades. RESULTS: Two hundred and ten aSAH patients underwent EVD treatment for a median 12 days (range 1-54); 85 required VPS (40%). On univariate analysis, EVD output, total EVD days, EVD days ≤ 5 mmHg, and wean/clamp trial failures were significantly associated with VPS placement (p < 0.01 for all parameters). No EVD output parameter demonstrated a significant association with DCI, RI, or SV. On multivariate analysis, EVD output was a significant predictor of VPS placement, after adjusting for age and clinical and radiological grades; the optimal threshold for predicting VPS placement was mean daily output > 204 ml on days 0-2 (OR 2.59, 95% CI 1.31-5.07). Multiple wean failures were associated with unfavorable functional outcome, after adjusting for age, grade, and VPS placement (OR 1.65, 95% CI 1.10-2.47). We developed a score incorporating age, grade and EVD parameters (MAGE) for predicting VPS placement after aSAH. CONCLUSIONS: EVD output parameters and wean/clamp trial failures predicted shunt dependence in an age- and grade-adjusted multivariable model. Early VPS placement may be warranted in patients with MAGE score ≥ 4, particularly following 2 failed wean trials.

Estrogen modulation of the cyclic AMP response element-binding protein pathway. Effects of long-term and acute treatments.

Actions of estrogen include mechanisms leading to alterations in gene transcription that may be independent of nuclear estrogen receptors, as well as those involving direct action of the estrogen receptor on the genome. Also, the influence of estrogen in the brain appears to extend well beyond areas associated with reproduction and may include forebrain areas linked to affective and cognitive behaviors. We investigated the effects of acute and long-term estradiol benzoate (E2) treatment on total and phosphorylated cyclic AMP responsive element-binding (CREB) protein levels and on cyclic AMP response element (CRE)-DNA binding in forebrain areas of ovariectomized (OVX) rats. Long-term E2 treatment increased CRE-DNA binding in the amygdala but not in hippocampus, frontal cortex, or cerebellum. The increase in CRE-DNA binding in the amygdala was associated with increased levels of total and phosphorylated CREB (pCREB) protein during protracted E2 exposure. To localize the estrogenic effect in the amygdala and determine if an effect in one hippocampal region was masked by a lack of effect in another subregion, we performed immunolabeling of pCREB in brain structures of chronically treated OVX animals with or without E2. This treatment resulted in a significant increase in relative total immunolabeled nuclei in the anteroventral subdivision of the medial amygdala. In the hippocampus, a significant increase in relative total immunolabeled nuclei was seen in the CA1 and CA3 regions, but not in the dentate gyrus or hilus of the dentate gyrus. Acute E2 treatment resulted in increased CRE-DNA binding in the frontal cortex but not in amygdala, hippocampus, or cerebellum. However, no changes in levels of total CREB or pCREB protein were observed in the frontal cortex under E2 treatment. No changes were observed either in basal or cAMP-stimulated protein kinase A (PKA) activity or in PKA-alpha catalytic subunit immunoreactivity in the amygdala or the frontal cortex. Our study indicates that both long-term and acute treatments with estrogens influence the function of CREB in specific brain structures.